This invention relates to improvements in and relating to contrast media, and in particular iodinated X-ray contrast media.
Contrast media may be administered in medical imaging procedures, for example X-ray, magnetic resonance and ultrasound imaging, to enhance the image contrast in images of a subject, generally a human or non-human animal body. The resulting enhanced contrast enables different organs, tissue types or body compartments to be more clearly observed or identified. In X-ray imaging, the contrast media function by modifying the X-ray absorption characteristics of the body sites into which they distribute.
Clearly however the utility of a material as a contrast medium is governed largely by its toxicity, by its diagnostic efficacy, by other adverse effects it may have on the subject to which it is administered, and by its ease of storage and ease of administration.
Since such media are conventionally used for diagnostic purposes rather than to achieve a direct therapeutic effect, when developing new contrast media there is a general desire to develop media having as little as possible an effect on the various biological mechanisms of the cells or the body as this will generally lead to lower animal toxicity and lower adverse clinical effects.
The toxicity and adverse biological effects of a contrast medium are contributed to by the components of the medium, e.g. the solvent or carrier as well as the contrast agent and its components (e.g. ions where it is ionic) and metabolites.
The following major contributing factors to contrast media toxicity and adverse effects have been identified:
the chemotoxicity of the contrast agent,
the osmolality of the contrast medium, and
the ionic composition (or lack thereof) of the contrast medium.
In coronary angiography, for example, injection into the circulatory system of contrast media has been associated with several serious effects on cardiac function. These effects are sufficiently severe as to place limitations on the use in angiography of certain contrast media.
In this procedure, for a short period of time a bolus of contrast medium rather than blood flows through the circulatory system and differences in the chemical and physicochemical nature of the contrast medium and the blood that it temporarily replaces can give rise to undesirable effects, e.g. arrhythmias, QT-prolongation, and, especially, reduction in cardiac contractile force and occurrence of ventricular fibrillation. There have been many investigations into these negative effects on cardiac function of infusion of contrast media into the circulatory system, e.g. during angiography, and means for reducing or eliminating these effects have been widely sought.
Early injectable ionic x-ray contrast agents, based on triiodophenylcarboxylate salts, were particularly associated with osmotoxic effects deriving from the hypertonicity of the contrast media injected.
This hypertonicity causes osmotic effects such as the draining out of water from red-blood cells, endothelial cells, and heart and blood vessel muscle cells. Loss of water makes red blood cells stiff and hypertonicity, chemotoxicity and non-optimal ionic make-up separately or together reduce the contractile force of the muscle cells and cause dilation of small blood vessels and a resultant decrease in blood pressure.
The osmotoxicity problem was addressed by the development of the non-ionic triiodophenyl monomers, such as iohexol, which allowed the same contrast effective iodine concentrations to be attained with greatly reduced attendant osmotoxicity effects.
The drive towards reduced osmotoxicity led in due course to the development of the non-ionic bis(triiodophenyl) dimers, such as iodixanol, which reduce osmotoxicity associated problems still further allowing contrast effective iodine concentrations to be achieved with hypotonic solutions.
This ability to achieve contrast effective iodine concentrations without taking solution osmolality up to isotonic levels (about 300 mOsm/kg H2O) further enabled the contribution to toxicity of ionic imbalance to be addressed by the inclusion of various plasma cations, as discussed for example in WO-90/01194 and WO-91/13636 of Nycomed Imaging AS.
However X-ray contrast media, at commercial high iodine concentrations of about 300 mgI/mL have relatively high viscosities, ranging from about 15 to about 60 mPas at ambient temperature with the dimeric media generally being more viscous than the monomeric media. Such viscosities pose problems to the administrator of the contrast medium, requiring relatively large bore needles or high applied pressure, and are particularly pronounced in paediatric radiography and in radiographic techniques which require rapid, bolus administration, e.g. in angiography.
In practice, viscosities in excess of 30 mPas at body temperature (37xc2x0 C.) are unacceptably high for routine X-ray investigations, and especially for paediatric investigations Accordingly, the maximum practical iodine concentration achievable with available non-ionic iodinated X-ray contrast agents is generally about 300-350 mgI/mL. Higher iodine concentrations, if accessible at acceptable viscosities, would increase the diagnostic efficacy of contrast enhanced images. Alternatively viewed, lower contrast medium viscosities for any given iodine concentration would increase ease of administration and the range of investigations and patients for which the contrast media could be used.
The present invention addresses the viscosity problem encountered with the prior art materials and thus viewed from one aspect the invention provides iodinated aryl compounds, useful as X-ray contrast agents, of formula I 
(wherein n is 0 or 1, and where n is 1 each C6R5 moiety may be the same or different; each group R is a hydrogen atom, an iodine atom or a hydrophilic moiety M or M1, two or three non-adjacent R groups in each C6R5 moiety being iodine and at least one, and preferably two or three, R groups in each C6R5 moiety being M or M1 moieties; X denotes a bond or a group providing a 1 to 7, for example 1, 2, 3 or 4 atom chain linking two C6R5 moieties or, where n is 0, X denotes a group R; each M independently is a non-ionic hydrophilic moiety; and each M1 independently represents a C1-4alkyl group substituted by at least one hydroxyl group and optionally linked to the phenyl ring via a carbonyl, sulphone or sulphoxide group, at least one R group, preferably at least two R groups and especially preferably at least one R group in each C6R5 moiety, being an M1 moiety; with the proviso that where n is zero either at least one M1 group other than a hydroxymethyl or 1,2-dihydroxyethyl (and optionally other than any hydroxyethyl) group is present or then if one hydroxymethyl or 1,2-dihydroxyethyl M1 group (and optionally any hydroxyethyl group) is present at least one nitrogen-attached hydroxylated alkyl (preferably C1-4-alkyl) moiety-containing M group is also present) and isomers, especially stereoisomers and rotamers, thereof.
It has also been found, surprisingly, that mandelic amides combine low viscosity and high hydrophilicity and a further aspect of the present invention provides iodinated aryl compounds, useful as X-ray contrast agents of formula I 
wherein n is 0 or 1, preferably 0, and where n is 1 each C6R5 moiety may be the same or different; X denotes a bond or a group providing a 1 to 7, for example 1, 2, 3 or 4 atom chain linking two C6R5 moieties or, where n is 0, X denotes a group R; each group R is a hydrogen atom, an iodine atom or a hydrophilic moiety M or M1, two or three non-adjacent R groups in each C6R5 moiety being iodine and at least one, and preferably two, more preferably three, R groups in each C6R5 moiety being M or M1 moieties; each M which may be the same or different, preferably being different, is a non-ionic hydrophilic moiety; and each M1 independently represents a xe2x80x94CHOHCON(R1)2 group wherein each R1, which may be the same or different, is a hydrogen atom, an OR group or a C1-6 alkoxy or optionally hydroxylated C1-5 alkyl group, preferably a hydrogen atom, at least one R group in the whole molecule and where n=1, preferably at least one R group in each C6R5 moiety, being an M1 moiety; and isomers thereof.
In a further aspect the invention provides a compound of formula C6R6 wherein three non-adjacent R groups are iodine and the remaining R groups are non-ionic, hydrophilic moieties, said compound being water soluble at 20xc2x0 C. to a concentration of at least 350 mgI/ml and which in aqueous solution at 20xc2x0 C. at a concentration of 350 mg I/ml has a viscosity no greater than 13.8 mPas.
In a yet further aspect, the invention provides a compound of formula C6R6 wherein three non-adjacent R groups are iodine and the remaining R groups are non-ionic, hydrophilic moieties, said compound being water soluble at 20xc2x0 C. to a concentration of at least 400 mgl/ml and which in aqueous solution at 20xc2x0 C. at a concentration of 400 mg I/ml has a viscosity no greater than 30.0 mPas.
It is found that the compounds of the invention exhibit advantageously low viscosity in aqueous solution; this is thought to derive from the presence of M1 groups on the phenyl groups, from compound asymmetry and, in the dimer compounds, from the nature of the linker X (especially where X provides a linkage less than 5 atoms in length).
The xcex1-hydroxyamide side chains are thought to contribute particularly to the low viscosity of compounds of the invention. These compounds of the invention have advantageously low viscosities as compared to current commercially available products for use as X-ray contrast agents. Low viscosity is a generally highly desirable property for X-ray contrast media, particularly so when the compounds are to be administered to children. These compounds of the invention will preferably have a viscosity of less than 20 more preferably less than 18, especially no more than 15 mPas in aqueous solution at 20xc2x0 C. and a concentration of 350 mgI/ml.
These compounds of the invention also exhibit an advantageously high hydrophilicity, and it is this combination of low viscosity and high hydrophilicity that makes the compounds of the invention so desirable for use in contrast media.
Thus for example all of the water-soluble monomer compounds according to the invention that have been tested have exhibited viscosities lower than that of iohexal.
The compounds of formula I are preferably asymmetric. For the monomer compounds (where n=0) this may be achieved by asymmetric substitution of the phenyl ring. For the dimers this can be achieved by the use of an asymmetric 2 or more atom chain-forming group X and/or by selection of non-identical C6R5 groups, i.e. by non-identical substitution of the iodophenyl end groups. Asymmetric molecules are preferred as they have been found to have better water-solubility.
Such non-identical substitution of the phenyl end groups, the C6R5 moieties, may be achieved by having different numbers or positions of iodine substitution and/or by different numbers, positions or identities of M or M1 substitution. To maximize iodine loading, triodophenyl end groups, i.e. groups of formula 
are preferred, and in these the two R groups may be the same or different, although preferably both represent M or M1 groups.
Where a phenyl end group is disubstituted by iodine, it is preferably of formula 
(where each M2 may be the same or different and represents an M1 or M group, at least one on each ring preferably representing an M1 group).
Generally, diiodophenyl-diiodophenyl dimers will be less preferred than the diiodophenyl-triiodophenyl or triiodophenyl-triiodophenyl diners, due primarily to their reduced iodine loading, i.e. 4 rather than 5 or 6 iodines per diner molecule. Indeed the triiodophenyl-triiodophenyl diners are generally preferred due to their higher iodine loading.
For the monomers, the triiodophenyl compounds are again preferred.
The solubilizing groups M may be any of the non-ionizing groups conventionally used to enhance water solubility. Suitable groups include for example a straight chain or branched C1-10-alkyl group, preferably a C1-5 group, optionally with one or more CH2 or CH moieties replaced by oxygen or nitrogen atoms and optionally substituted by one or more groups selected from oxo, hydroxy, amino, carboxyl derivative, and oxo substituted sulphur and phosphorus atoms. Particular examples include polyhydroxyalkyl, hydroxyalkoxyalkyl and hydroxypolyalkoxyalkyl and such groups attached to the phenyl group via an amide linkage such as hydroxyalkylaminocarbonyl, N-alkyl-hydroxyalkylaminocarbonyl and bis-hydroxyalkylaminocarbonyl groups. Preferred among such groups are those containing 1, 2, 3, 4, 5 or 6, especially 1, 2 or 3, hydroxy groups, e.g.
xe2x80x94CONHxe2x80x94CH2CH2OH
xe2x80x94CONHxe2x80x94CH2CHOHCH2OH
xe2x80x94CONHxe2x80x94CH (CH2OH)2 
xe2x80x94CON(CH2CH2OH)2 
as well as other groups such as
xe2x80x94CONH2 
xe2x80x94CONHCH3 
xe2x80x94OCOCH3 
xe2x80x94NHCOCH2OH
xe2x80x94NHCOCHOHCH3 
xe2x80x94NH(COCHOHCH2OH)
xe2x80x94NH(COCHOHCHOHCH2OH)
xe2x80x94NH(COCHOHCHOHCH3)
xe2x80x94NH(COCHOHCH2CH2OH)
xe2x80x94NH(COCH(CH2OH)2)
xe2x80x94N(CH3)COCHOHCH2OH
xe2x80x94N(CH3)COCHOHCHOHCH2OH
xe2x80x94N(CH3)COCHOHCHOHCH3 
xe2x80x94N(CH3)COCHOHCH2CH2OH
xe2x80x94N(CH3)COCH(CH2OH)2 
xe2x80x94N(COCH3)H
xe2x80x94N(COCH3)C1-3-alkyl
xe2x80x94N(COCH3)-mono, bis or tris-hydroxy C1-4-alkyl
xe2x80x94N(COCH2OH)-mono, bis or tris-hydroxy C1-4-alkyl
xe2x80x94N(COCH2OH)2 
xe2x80x94CON(CH2CHOHCH2OH)(CH2CH2OH)
xe2x80x94CONHxe2x80x94C(CH2OR)3 and
xe2x80x94CONHxe2x80x94CH(CH2OH)(CHOHCH2OH)
xe2x80x94CON(CH3)CH2CH2OH
xe2x80x94CON(CH3)CH2CHOHCH2OH.
In general, the M groups will preferably each comprise a mono-or polyhydroxy C1-4-alkyl group such as 1,3-dihydroxyprop-2-yl or 2,3-dihydroxyprop-1-yl, attached to a primary amide group, wherein the primary amide group is linked to the phenyl ring by either the carbon atom in the carbonyl group or by the nitrogen.
For those compounds of the invention wherein M1 represents a xe2x80x94CHOHCON(R1)2 group as previously is defined, one or more of the M groups may be a C1-4 alkyl group substituted by at least one hydroxyl group and optionally linked to the phenyl ring via a carbonyl group, preferably xe2x80x94CH2OH or a propanediol.
Other such M groups as are conventional within the field of triiodophenyl X-ray contrast agents may also be used and the introduction of M groups onto iodophenyl structures may be achieved by conventional techniques.
Typically, the monomers of the present invention will contain one M1 group though they may contain two or three M1 groups, similarly the dimers will typically contain one M1 group per C6R5 moiety but each C6R5 moiety may have two or three M1 groups.
For the compounds of the invention first described, M1 groups preferably comprise C1-4-alkyl groups substituted by 1, 2, 3 or 4 hydroxy groups (e.g. hydroxymethyl, 2-hydroxyethyl, 2,3-bishydroxy-propyl, 1,3-bishysdroxyprop-2-yl, 2,3,4-trihydroxybutyl, and 1,2,4-trihydroxybut-2-yl) optionally connected to the phenyl ring via a CO, SO or SO2 group (e.g. COCH2OH or SO2CH2OH).
In the dimeric compounds of the invention, the linker group X is conveniently a bond or a 1 to 7, e.g. 1, 2, 3 or 4, membered chain comprising carbon, nitrogen, oxygen or sulphur atoms, e.g.
a bond,
a O, S, N or C one atom chain,
a NN, NC, NS, CC or CO two atom chain,
or a NCN, OCN, CNC, OCO, NSN, CSN, COC, OCC or CCC three atom chain,
for example:
an oxygen atom or a group NR1, CO, SO2 or CR21;
a group COCO, CONR1, COCR21, SOCR21, SO2NR1, CR21CR21, CR21NR1 or CR12O;
a group NR1CONR1, OCONR1, CONR1CO, CONR1CR12, OCOO, CR12OCR12, OCR12CO, CR12CONR1, CR12CR12CR12, COCR1R1CO, CR12NR1CR12, CR12SO2NR1, CR12OCO or NR1SO2NR1;
where R1 is hydrogen or a C1-6-alkyl or alkoxy group optionally substituted by hydroxy, alkoxy, oxa or oxo (e.g. a polyhydroxyalkyl, formyl, acetyl, hydroxyl, alkoxy or hydroxyalkoxy group) and where it is attached to a carbon atom R1 may also be a hydroxyl group.
Where X is a 2-7 membered chain it is preferably non-symmetric.
When X provides a 4-7 atom linkage, conventional linker groups, such as for example those suggested by Justesa in WO-93/10078 or Bracco in U.S. Pat. No. 4,348,377 and WO-94/14478 may be used.
In general such linkages will comprise optionally aza or oxa substituted alkylene chains optionally carrying R1 substituents, especially such groups terminating with imine nitrogen or, more preferably, carbonyl carbon atoms, preferably belonging to aminocarbonyl functional units within the chain. Hydroxylated chains, such as are found in iodixanol are particularly preferred.
Examples of such chains are NCCN, NCCCN, CNCCCNC, and CNCCN, eg.
xe2x80x94NR1COCONR1xe2x80x94
xe2x80x94NR1COCR12CONR1xe2x80x94
xe2x80x94NR1CR12CR1OHCR12NR1xe2x80x94
xe2x80x94CONR1CR12CONR1xe2x80x94 and
xe2x80x94N(COR1)CR12CR1OHN(COR1)xe2x80x94,
e.g. as found in iotrolan, iofratol, ioxaglic acid and iodixanol, or as otherwise indicated in WO-94/14478.
Advantageously, in the diner compounds the X group is not symmetrical. This may be achieved for example by asymmetrical substitution of a symmetrical chain (e.g. Nxe2x80x94Cxe2x80x94N substituted as NHCONR1) or by selection of an asymmetric chain (e.g. OCN substituted as OCONR1). In particular, it is preferred that the linker group X should be polar and also that it should be hydrophilic.
Thus examples of preferred structures according to the intention include: 
where each M2 is M1 or M, at least one in each compound (and preferably on each ring) being M1, especially where at least one M2 is a C1-4-alkyl group substituted by 1, 2, 3 or 4 hydroxy groups (e.g. hydroxymethyl, 2-hydroxyethyl, 2,3-bishydroxy-propyl, 1,3-bishydroxyprop-2-yl, 2,3,4-trihydroxybutyl, and 1,2,4-trihydroxybut-2-yl) optionally connected to the phenyl ring via a CO, SO or SO2 group (e.g. COCH2OH or SO2CH2OH), e.g. a hydroxyalkyl or hydroxyalkylcarbonyl group, in particular a hydroxymethyl, hydroxymethylcarbonyl, 2-hydroxyethyl or 2-hydroxyethylcarbonyl group, and where R1 is hydrogen, hydroxyl, hydroxyalkyl (eg. 2-hydroxyethyl), acetyl or hydroxyalkylcarbonyl.
Particular preferred compounds are those of formula 
It is especially preferred that a hydroxymethyl M1 group be present in the compounds of the invention and in particular that the compounds be hydroxymethyl substituted monomers
Thus viewed from a further aspect the invention provides compounds of formula II 
where each R group, which may be the same or different, is a non-ionic hydrophilic moiety (e.g. as defined above, preferably a group containing up to 10, more preferably 1 to 6, especially 2 to 4 hydroxyl groups), or one R group may be a second non-ionic triiodophenyl group, attached directly or via a non-ionic organic linker moiety.
Preferably the compounds of formula II are monomeric and especially preferably the two R groups are hydroxylated alkylcarbonylamino or hydroxylated alkylaminocarbonyl groups wherein the alkyl moieties contain 1 to 6 carbons and the amide nitrogens are optionally alkylated by optionally hydroxylated C1-6 groups.
It has surprisingly been found that where the triiodophenyl ring carries a hydroxymethyl substituent, i.e. a small mono-hydroxylated group, especially high iodine concentrations can be achieved at relatively low or acceptable viscosities.
Thus viewed from a further aspect the invention provides a non-ionic iodinated X-ray contrast agent compound comprising a 1-hydroxymethyl-2,4,6-triiodobenzene ring structure, having a water solubility of at least 400 mgI/mL at 20xc2x0 C., and having a viscosity of less than 30 mPas in aqueous solution at 20xc2x0 C. and a concentration of 400 mgl/mL, preferably having a viscosity of less than 30 mPas in aqueous solution at 20xc2x0 C. and a concentration of 450 mgI/mL.
Particularly preferably, the compounds have viscosities at 400 mgI/mL aqueous solution at 20xc2x0 C. of less than 20 mPas.
Viewed from a further aspect the invention provides non-ionic 2,4,5-triiodobenzyl alcohols having a nitrogen attached substituent, preferably a hydroxylated substituent, at at least one of the 3- and 5-positions.
Particularly preferably the compounds of the invention have the formula III 
where R7 and R8, which may be the same or different, are CH2OH, R10CONR9 or R10CONR9; each R9, which may be the same or different, is hydrogen or a linear or branched hydroxylated C1-6 alkyl; and each R10 which may be the same or different is a linear or branched hydroxylated C1-6 alkyl.
Examples of suitable R9 and R10 groups include H, CH2OH, CHOHCH3, CH2CH2OH, CHOHCH2OH, C(CH3)(CH2OH)2, C(CH2OH)2, CH2CHOHCH2OH and CH(CH2OH)CHOHCH2OH.
Examples of suitable R10CONR9 groups include HOCH2CON(CH2CHOHCH2OH), HOCH2CONH, HOCH2CON(CH2CH2OH), CH3CHOHCONH, CH3CHOHCON(CH2CH2OH), CH3CHOHCON(CH2CHOHCH2OH), HOCH2CHOHCONH, HOCH2CHOHCON(CH2CH2OH), OHCH2CHOHCON(CH2CHOHCH2OH), (CH2OH)2(CH3)CCONH, (CH2OH)2CHCONH, HOCH2CH2CONH, (CH2OH)3CCONH, HOCH2CON(CH2CHOHCH2OH), and HOCH2CHOHCHOHCONH.
Examples of particularly suitable R10N(R9)CO groups include HOCH2CHOHCH2NHCO and, HOCH2CHOHCH(CH2OH) NHCO, (HOCH2CH2)2NCO, HOCH2CHOHCH2N(CH3)CO, (HOCH2)2CHNHCO, HOCH2CH2NHCO, and (HOCH2)3CNHCO.
Further preferred compounds include those of formula IV 
wherein R11 and R12, which may be the same or different are groups R10CONR9 or R10NR9CO as defined above with the proviso that at least one is a group R10CONR9.
In the compounds of formulae III and IV, and indeed in all the compounds according to the invention, the triiodophenyl ring substituents preferably carry a total of 4 to 7 hydroxyl groups.
In the compounds of formula III, conveniently: (i) one of R7 and R8 is N attached (and the other is CO attached) and the R10CO group is hydroxylated; (ii) both R7 and R8 are CO attached; or (iii) both R7 and R8 are nitrogen attached and at least one R10 is other than HOCH2, HOCH2CHOH or CH3CHOH.
Preferably the compounds of the invention are monomers, i.e. n=0, and preferred among the mandelic amide compounds of the invention are those of formula IIxe2x80x2
wherein each group Rxe2x80x2 is a hydrogen atom or a hydrophilic moiety M or M1 as previously defined and R1 is as previously defined. Preferably each group Rxe2x80x2 is an M or M1 moiety.
Particularly preferred among the mandelic amide compounds of the invention are compounds of formulae IIIxe2x80x2, IVxe2x80x2 and Vxe2x80x2. 
wherein R1 is as previously defined and each R2 which may be the same or different is a C1-4 hydroxyalkyl group, preferably at least one R2 group is a C2-4 polyhydroxyalkyl group.
The two R2 groups between them will preferably contain 3 to 5, more preferably 4 hydroxyl groups. The preferred number of hydroxyl groups will typically depend on the contribution to water solubility of the R1 group and can therefore be adjusted accordingly.
In the compounds of formula Vxe2x80x2, the R2 groups preferably each contain an even number of hydroxyl groups.
In the compounds of formula IVxe2x80x2, the R2 groups are preferably different.
Especially preferred compounds of the invention include,
(N,Nxe2x80x2-bis(hydroxyacetyl)-3,5-diamino-2,4,6-triiodomandeloamide),
(N-(2,3-dihydroxypropionyl)-Nxe2x80x2-hydroxyacetyl-3,5-diamino-2,4,6-triiodomandeloamide);
(N,Nxe2x80x2-bis(2,3-dihydroxypropionyl)-3,5-diamino-2,4,6-triiodomandeloamide),
(N-(2,3,4-trihydroxybutyryl)-Nxe2x80x2-hydroxyacetyl-3,5-diamino-2,4,6-triiodomandeloamide), particularly (N-(2R,3S,4-trihydroxybutyryl)-Nxe2x80x2-hydroxyacetyl-3,5-diamino-2,4,6-triiodomandeloamide) and (N-(2R,3R,4-trihydroxybutyryl)-Nxe2x80x2-hydroxyacetyl-3,5-diamino-2,4,6-triiodomandeloamide),
(N,Nxe2x80x2-bis(2,3-dihydroxybutyryl)-3,5-diamino-2,4,6-triiodomandeloamide),
(N,Nxe2x80x2-bis(2,4-dihydroxybutyryl)-3,5-diamino-2,4,6-triiodomandeloamide),
(N,Nxe2x80x2-bis(2,2-bis(hydroxymethyl)-acetyl)-3,5-diamino-2,4,6-triiodomandeloamide),
(N,Nxe2x80x2-bis(2,3,4-trihydroxybutyryl)-3,5-diamino-2,4,6-triiodomandeloamide), particularly (N,Nxe2x80x2-bis(2R,3S,4-trihydroxybutyryl)-3,5-diamino-2,4,6-triiodomandeloamide), and
(5-(2,3-dihydroxypropionyl)amino-3-N-(2,3-dihydroxypropyl)carbamido-2,4,6-triiodomandeloamide).
An especially preferred compound is N-(2R,3S,4-trihydroxybutyryl)-Nxe2x80x2-hydroxyacetyl-3,5-diamino-2,4,6-triiodomandelamide.
It should be appreciated that the invention relates to all stereoisomeric forms of a given compound of formula I as defined herein The M1 group of the mandelic amides as defined herein contains one chiral center and M groups may also have chiral centers, giving rise to different diastereomers and enantiomers. In general, the physical and biological properties of the different stereoisomers do not differ widely and a is particular contrast medium may contain a mixture of isomers of the active ingredient. In certain circumstances, e.g. relating to obtaining regulatory approval, it may be more convenient to prepare a contrast agent which contains a limited number of stereoisomers. Restrictions on the stereoisomers present in the final contrast medium may typically be a result of the chosen starting material which may be readily available in enantiomerically pure form.
The compounds of the invention may be prepared by any of the methods of synthesis of organic molecules known in the art and described in the literature. Advantageously, where appropriate, the compounds may be prepared by initial formation of a mandelic amide, then iodination of the phenyl ring and finally substitution of the phenyl ring with the solubilising groups M. Where desired the linker group X may be produced by modification, e.g. substitution, oxidation or reduction, of a precursor linker, e.g. in a precursor monomer.
The compounds of the invention may be prepared by removal of a hydroxy or amino protecting group from a compound of formula I which additionally incorporates such a protecting group. Such a method of preparation constitutes a further aspect of the present invention.
A typical reaction scheme for the preparation of a compound according to the invention is shown below 
The compounds of the invention may in general be prepared in two or three stages: (a) dimer formation (where necessary), (b) iodination of phenyl groups and (c) substitution of phenyl groups and/or optionally linker moieties by solubilizing moieties.
While, in theory, stages (a), (b) and (c) can be performed in any order, it will generally be preferred to perform the dimer formation step before the iodination step and, for reasons of economy, it will be preferred to perform the iodination step at as late a stage in the synthesis as is feasible so as to reduce iodine wastage. The diner formation stage may itself be a multi-step procedure with an appropriate activated linker first being attached to one monomer before the resulting linker-monomer conjugate is reacted with a second monomer. Alternatively, dimer formation may be by way of reaction of similarly or cooperatively substituted monomers with the conjugation of the monomers leading to diner formation.
Where desired the linker group X may be produced by modification, e.g. substitution, oxidation or reduction, of a precursor linker, e.g. in a precursor monomer.
For the monomer compounds, especially those where ring substitution is asymmetric, iodine loading will generally be effected before or after partial substitution of the phenyl ring with R groups.
In all cases, conventional synthetic routes well known in the literature (eg methods analogous to those used and described for the production of the compounds referred to in WO-94/14478) may be used.
The compounds of the invention may be used as X-ray contrast agents and to this end they may be formulated with conventional carriers and excipients to produce diagnostic contrast media.
Thus viewed from a further aspect the invention provides a diagnostic composition comprising a compound of formula I together with at least one physiologically tolerable carrier or excipient, e.g. in aqueous solution in water for injections optionally together with added plasma ions or dissolved oxygen.
The contrast agent compositions of the invention may be at ready-to-use concentrations or may be formulated in concentrate form for dilution prior to administration. Generally compositions in ready-to-use form will have iodine concentrations of at least 100 mgI/ml, preferably at least 150 mgI/ml, with concentrations of at least 300 mgI/ml, e.g. 320 to 600 mgI/ml or 400 to 550 mgI/ml being generally preferred. The higher the iodine concentration the higher the diagnostic value but equally the higher the solution""s viscosity and osmolality. Normally the maximum iodine concentration for a given compound will be determined by its solubility, and by the upper tolerable limits for viscosity and osmolality.
For contrast media which are administered by injection, the desirable upper limit for solution viscosity at ambient temperature (20xc2x0 C.) is 30 mPas; however viscosities of up to 50 or even up to 60 mPas can be tolerated although their use in paediatric radiography will then generally be contraindicated. For contrast media which are to be given by bolus injection, e.g. in angiographic procedures, osmotoxic effects must be considered and preferably osmolality should be below 1 Osm/kg H2O, especially below 850 mOsm/kg H2O.
With the compounds of the invention, such viscosity, osmolality and iodine concentration targets can readily be met. It may however be desirable to include plasma cations for their cardioprotective effect. Such cations will desirably be included in the ranges suggested in WO-90/01194 and WO-91/13636.
Preferred plasma cation contents for the contrast media of the invention, especially contrast media for angiography, are as follows:
sodium 2 to 100, especially 15 to 75, particularly 20 to 70, more particularly 25 to 35 mM
calcium up to 3.0, preferably 0.05 to 1.6, especially 0.1 to 1.2, particularly 0.15 to 0.7 mM
potassium up to 2, preferably 0.2 to 1.5, especially 0.3 to 1.2, particularly 0.4 to 0.9 mM
magnesium up to 0.8, preferably 0.05 to 0.6, especially 0.1 to 0.5, particularly 0.1 to 0.25 mM
The plasma cations may be presented, in whole or in part, as counterions in ionic contrast agents. Otherwise they will generally be provided in the form of salts with physiologically tolerable counteranions, e.g. chloride, sulphate, phosphate, hydrogen carbonate, etc., with plasma anions especially preferably being used.
Besides plasma cations, the contrast media may contain other counterions where the compound of formula I is ionic and such counterions will of course preferably be physiologically tolerable. Examples of such ions include alkali and alkaline earth metal ions, ammonium, meglumine, ethanolamine, diethanolamine, chloride, phosphate, and hydrogen carbonate. Other counterions conventional in pharmaceutical formulation may also be used. The compositions moreover may contain further components conventional in X-ray contrast media, e.g. buffers, etc.
Viewed from a still further aspect the present invention provides a method of generating an enhanced image of at least part of a human or non-human animal body which comprises administering to said body a compound of formula I and generating an image of at least part of said body to which said compound distributes.
In a yet further aspect, the invention provides the use of a compound of formula I for the manufacture of a diagnostic composition for use in a method of diagnosis which involves generating an image.
Publications referred to herein are incorporated herein by reference.